Resent research has clarified that nitric oxide (NO) is the very vascular endothelium-derived relaxing factor (EDRF) and that it is functioning as a chemical transmitter or modulator not only in vascular endothelial cells but also in such other cells or tissues as the brain, platelet, macrophage, neutrophil, and non-adrenergic, non-cholinergic nervous systems. This nitric oxide is produced by NO synthase using L-arginine (L-Arg) as the substrate. It has been reported that said NO synthase has at least two iso-forms. One is a constitutive-type enzyme which occurs in the vascular endothelium and the brain. The other is an inducible type-enzyme which occurs in the macrophage and vascular smooth muscle. Meanwhile, it is known that the above inducible-type NO synthase is induced by a variety of cytokines such as interleukins (ILs), interferon-.gamma. (IFN-.gamma.), tumor necrosis factor (TNF), etc., or by endotoxins and a broad spectrum of cytokines derived from endotoxins.
It has also been reported that in the event an excess of said nitric oxide is produced and released in the body, various cells and tissues are injured not only by its inherent blood vessel-relaxing effect but also by the chemical reactivity of nitric oxide itself. In particular, it is known that the above-mentioned inducible NO synthase, which is known to be induced by endotoxins and various cytokines, is deeply associated, through the nitric oxide it produces, with the onset and morbidity of endotoxin shock and bleeding tendency. The inducible NO synthase attracts attention in connection with its relation to such morbidity, rather than the physiological roles it plays.
Meanwhile, a variety of inhibitor substances that inhibit synthesis of said nitric oxide are also known and the inhibitors which are most widely used today are various L-arginine derivatives having a methyl or nitro group in the .omega.-position (guanidino group) of L-arginine (L-Arg), which are reversible or irreversible competitive inhibitors of NO synthase for the L-Arg substrate.
Refer to the following reference documents regarding the prior mentioned above for more information.
(1) Hideki Moritoki: Blood Vessel and Endothelium, Vol. 2, No. 4 p. 32-40, 1992 PA0 (2) Takaaki Akaike et al.: Advances in Medicine, Vol. 166, No. 3, p. 161-164, 1993, 7, 17 PA0 (3) Hideki Moritoki, et al., Br. J. Pharmacol., (1991), 102, 841-846 PA0 (4) Hideki Moritoki, et al., Br. J. Pharmacol., (1992), 107, 361-366